Sustained release medicinal compositions

ABSTRACT

The present invention relates to sustained-release pharmaceutical compositions for ionic pharmaceutically active substances (excluding ionic prostanoic acid derivatives) containing ionic compounds having opposite charges to those of the active substances and increasing hydrophobicity of the active substances. More specifically, the invention relates to sustained-release pharmaceutical compositions comprising the ionic pharmaceutically active substances and the ionic compounds having opposite charges to those of the active substances and increasing hydrophobicity of the active substances that contain hydrophobic groups in the molecule thereof. The pharmaceutical composition of the invention can exhibit excellent sustained release effect of the active substance, irrespective of water solubility possessed by the ionic pharmaceutically active substances.

FIELD OF THE INVENTION

The present invention relates to a sustained-release pharmaceuticalcomposition for an ionic pharmaceutically active substance (excluding anionic prostanoic acid derivative). More particularly, the inventionrelates to a sustained-release pharmaceutical composition comprising anionic pharmaceutically active substance and an ionic compound which hasan opposite charge to that of the ionic pharmaceutically activesubstance and enhances the hydrophobic property of the ionicpharmaceutically active substance.

RELATED ART

Oral administration has been widely applied to delivery ofpharmaceutically active substances. While there is a need forfast-acting drugs, both fast and continuously acting drugs aresimultaneously necessary sometimes. In this case, parenteraladministration is generally used in combination with oraladministration. For parenteral preparations, there are knownintravenous, subcutaneous or intramuscular injection; implants andtransmucosal preparations through oral cavity, nasal cavity, lung,vagina, rectum, skin, etc. Of these routes, injection is a generalchoice for administration.

However, sustained release of some medicaments may cause difficulty inparenteral preparations, depending upon the property of apharmaceutically active substance. For example, such difficulty is notedwith pharmaceutically active substances having a short half life inblood, a high water solubility or a low molecular weight. When it isdesired to maintain the pharmacological effects of those medicamentsover a long period of time, it is the actual practice to administer sucha medicament by instillation through the vein or frequently inject themedicament subcutaneously or intramuscularly. A burden of such atreatment is not negligible to patients either physically or mentally.To solve the problem, it has been investigated to create apharmaceutically active substance having a prolonged half life in bloodor to produce a hybrid between a pharmaceutically active substance and ahigh molecular weight substance such as polyethylene glycol byirreversible bonding of the two substances, thereby to extend the halflife of the pharmaceutically active substance itself in blood. Variousother techniques for controlling the solubility or dissolution of apharmaceutically active substance out of a carrier have been studied,which involve insolubilizing or sparingly solubilizing apharmaceutically active substance in water to delay its dissolution, ormicroencapsulation of a pharmaceutically active substance using abiodegradable high molecular weight material.

For example, Japanese Patent Application Laid-Open No. 1-163199discloses that an organic acid with a high molecular weight of about5,000 or more, e.g., sodium alginate, is added to a cytokine likeinterleukin 2 so as to reach the isotonic osmotic pressure or more andthe mixture is then shaken to form the water-insoluble matter, wherebythe insoluble mater is used in a sustained-release composition forinjection.

Japanese Patent Application Laid-Open No. 9-208485 discloses asustained-release preparation comprising a sparingly water-solublecomposition formed from a peptide-proteinaceous medicament and EDTA.

Japanese Patent Application Laid-Open Nos. 8-3055 and 8-217691 disclosesustained-release preparations comprising microcapsules obtained bymixing a water-soluble pharmaceutically active substance and awater-soluble polyvalent metal salt, and dispersing the resultingwater-insoluble mixture of in a biodegradable high molecular weightmaterial such as polylactic acid-glycolic acid copolymer.

On the other hand, Japanese Patent Application Laid-Open No. 62-129226discloses that hyaluronic acid or its sodium salt, or Hylan enables amedicament dissolved or dispersed in the solution to achieve continuousrelease from the solution mainly based on the viscosity of the solution.This publication also discloses that in a cationic group-containingmedicament, exchange of ions could occur between this carboxylgroup-containing macromolecule of hyaluronic acid and the medicament,where the exchange causes slower diffusion of the medicament out of thesystem. As a technique utilizing the viscosity of hyaluronic acid,Japanese Patent Application Laid-Open No. 1-287041 discloses asustained-release preparation suitable for subcutaneous or intramuscularadministration, comprising a pharmaceutically active substance andhyaluronic acid or a salt thereof; Japanese Patent Application Laid-OpenNo. 2-213 also discloses a sustained-release preparation comprising aphysiologically active peptide and hyaluronic acid or a salt thereof

However, such a sustained-release preparation utilizing the viscosity ofhyaluronic acid provides a fast diffusion of a pharmaceutically activesubstance from the viscous product, in which the active substance isincorporated. Even taking into account the ionic interaction abilitybetween hyaluronic acid and a cationic medicament coupled to theviscosity of hyaluronic acid, it is suspected that retardation indissolution is not enough. Yet, any sustained-release parenteralpreparation that is satisfactory from a clinical standpoint has beenunknown for not only cationic but also ionic pharmaceutically activesubstances. Particularly in the case of a highly water-soluble ionicpharmaceutically active substance, sustained release could not beattained to a satisfactory extent by the prior art technique ofretarding the diffusion using the viscosity of a high molecular weightsubstance, especially because of its high water solubility.

Japanese Patent Application Laid-Open No. 53-18723 discloses acomposition for rectal administration obtained by intimately mixinginsulin with a quaternary ammonium salt cationic surfactant. JapanesePatent Application Laid-Open No. 59-89619 discloses a liquidpharmaceutical composition for nasal administration, comprisingcalcitonin and benzalkonium chloride in a liquid diluent or carriersuitable for application to nasal mucous membrane. However, thetechniques described in these gazette publications all aim at improvingabsorption of a medicament by rectal administration or nasaladministration but none of the publications mentions or even suggestssustained release of a medicament involving the imparted hydrophobicproperty of an ionic complex.

DISCLOSURE OF THE INVENTION

An object of the present invention is to provide a sustained-releasepreparation of an ionic pharmaceutically active substance, irrespectiveof water solubility of the active substance, to such an extent that issatisfactory for clinical use.

Under the foregoing technical level, the present inventors attempted toprovide a sustained-release preparation for an anionic pharmaceuticallyactive substance, for which sustained release is required throughparenteral route, first by adding an equimolar amount of a cationiccompound to the anionic pharmaceutically active substance and forming asparingly water-soluble ionic complex through ionic interaction betweenthe anionic and cationic compounds, with an expectation to achieve asustained release. However, subcutaneous administration of the ioniccomplex formed to rats revealed that no satisfactory sustained-releasewas obtained. It was thus found that the retarded dissolution of anionicpharmaceutically active substances is insufficient for the purpose ofsustained release of ionic pharmaceutically active substances byparenteral route.

In order to further increase the hydrophobicity of the pharmaceuticallyactive substance accompanied by the formation of the ionic complex, thepresent inventors have brought attention to an octanol/water partitioncoefficient as an index for the hydrophobicity. As a result, it has beenfound that depending upon kind of the cationic compound, there is adifference in the partition coefficient of the cationic pharmaceuticallyactive substance associated with the ionic complex formation and that abetter sustained release effect is obtained with a larger partitioncoefficient. It has also been found that the sustained release effectcan be more enhanced by increasing the addition amount of the cationiccompound and increasing the partition coefficient for the anionicpharmaceutically active substance. Furthermore, it has been discoveredthat these ionic complexes unexpectedly exhibit an excellent sustainedrelease effect, even when a dissolved state of the pharmaceuticallyactive substance in water is maintained, that is, the state of itsaqueous solution is maintained if the pharmaceutically active substanceis water-soluble.

The present inventors have confirmed that a sustained release of theionic pharmaceutically active substance attained by increasing thehydrophobic level of a pharmaceutically active substance is effectivefor not only an anionic pharmaceutically active substance but also avariety of cationic medicaments. It was hitherto unknown that asustained release can be attained by the increased hydrophobic level ofionic pharmaceutically active substances. Based on the finding that sucha technique is advantageously applicable not only to parenteralpreparations but to oral preparations, the present invention has beenfound.

(1) That is, the present invention relates to a sustained-releasepharmaceutical composition comprising an ionic pharmaceutically activesubstance (excluding an ionic prostanoic acid derivative) and an ioniccompound having an opposite charge to that of the ionic pharmaceuticallyactive substance and increasing hydrophobicity of the active substance.

(2) The present invention also relates to a sustained-releasepharmaceutical composition according to (1), wherein the ionic compoundhaving an opposite charge to that of the ionic pharmaceutically activesubstance and increasing the hydrophobic property of the activesubstance contains a hydrophobic group in the molecule thereof.

(3) The present invention also relates to a sustained-releasepharmaceutical composition according to (1) or (2), wherein the ioniccompound increases an oil/water partition coefficient of the ionicpharmaceutically active substance.

(4) The present invention further relates to a sustained-releasepharmaceutical composition according to any one of (1) to (3), whereinthe ionic compound is incorporated at least in an equimolar amount basedon the pharmaceutically active substance in terms of a charge ratio.

The sustained-release pharmaceutical composition of the presentinvention is characterized in that by adding a particular counter ion tothe ionic pharmaceutically active substance to increase the oil/waterpartition coefficient of the ionic pharmaceutically active substance, ahydrophobic property is imparted to give the sustained-releasepharmaceutical composition of the invention suitable for, e.g.,injection. The sustained release according to the present invention iseffected by means of a novel method quite different from conventionaltechniques adopted to control the release of ionic pharmaceuticallyactive substances, to insolubilize a pharmaceutically active substanceitself, to retard the dissolution of the active substance bymicroencapsulation, etc.. Moreover, the present invention ischaracterized in that the sustained release can be achieved in thepresent invention to a fully satisfactory extent that was obtained onlyinsufficiently by these known means.

The sustained-release pharmaceutical composition of the presentinvention will be described below in more detail.

The ionic pharmaceutically active substance used in the presentinvention is not particularly limited, so long as the substance isprovided generally pharmacologically for a treatment and its sustainedrelease is desired for oral or parenteral administration. Examples ofthe anionic pharmaceutically active substance include antipyreteic andantiinflammatory agents such as fulfenamic acid, mefenamic acid,salicylic acid, indomethacin, alclofenac, diclofenac, alminoprofen,ibuprofen, etodolac, oxaprozin, ketoprofen, diflunisal, sulindac,tiaprofen, tolmetin, naproxen, calcium fenoprofen, pranoprofen,flurbiprofen, sodium roxoprofen, lobenzarit disodium, etc.; hypnotictranquilizers such as sodium amobarbital, etc.; local anesthetics suchas hopantenic acid, etc.; muscle relaxants such as dantrolene, etc.,antispasmodic agents such as baclofen, etc.; antidiuretic agents such asfurosemide, etacrynic acid, piretanide, etc.; antihypertensive agentssuch as captopril, enalapril, methyldopa, etc.; antihyperlipemic agentssuch as pravastatin, hormones such as liothyronine, levothyroxine,betamethasone phosphate, prednisolone succinate, etc.; bone metabolismimproving agents such as minodronic acid, etc.; hemostatic agents suchas carbazochrome sulfate, thrombin, tranexamic acid, etc.; medicamentsfor the treatment of gout such as probenecid, etc.,metabolism-associated agents such as chondroitin sulfate, adenosinetriphosphoate, etc.; antiallergic agents such as cromoglicic acid,tranilast, etc.; antibiotics such as ampicillin, cefaclor, cefalexin,cefpiramid, cefotetan, etc.; anti-tuberculosis agents such asp-aminosalicylic acid, etc.; medicaments for blood and body fluids;medicaments for the treatment of liver disorders such as glucuronicacid, etc.; vitamins such as biotin, calcium pantothenate, etc. Theseanionic pharmaceutically active substances may be in the form ofpharmaceutically acceptable salts thereof or free acids thereof.

The anionic pharmaceutically active substances may also be associatedwith expression of peptides, for example, nucleic acids such as DNA,RNA, etc., transcription regulators of a high or low molecular weightand inhibitors thereof.

The cationic pharmaceutically active substances includeanti-parkinsonism agents such as amantadine hydrochloride, biperidenehydrochloride, etc.; psychotropic agents such as chlorpromazinehydrochloride, perphenazine, perphenazine maleate, imipraminehydrochloride, amitriptyline hydrochloride, etc.; local anesthetics suchas procaine hydrochloride, lidocaine hydrochloride, dibucainehydrochloride, etc.; muscle relaxants such as suxamethonium chloride,etc.; agents for the autonomic nervous system such as acetylcholinechloride, methylbenactyzium bromide, distigmine bromide, torazolinehydrochloride, etc.; antispasmodic agents such as scopolaminehydrobromide, atropine sulfate, etc., agents for the treatment ofarrhythmia such as procainamide hydrochloride, etc.; circulatory agentssuch as hydralazine hydrochloride, bencyclan fumarate, etc.;antihypertensive agents such as amosulalol hydrochloride, nicardipinehydrochloride, betanidine sulfate, etc.; vasodilating agents such asdiltiazem hydrochloride, etc.; antitussive agents such as ephedrinehydrochloride, dl-methylephedrine hydrochloride, etc.; agents for thetreatment of peptic ulcer such as famotidine, etc.; urogenital agentssuch as tamsulosin hydrochloride, etc.; anti-vomiting agents such asramosetron hydrochloride, etc.; agents for blood and body fluids such asticlopidine hydrochloride, etc.; alkylating agents such ascyclophosphamide, etc.; antihistaminic agents such as diphenhydraminehydrochloride, chlorpheniramine maleate, etc.; antibiotics such astalampicillin hydrochloride, etc.; antitumor antibiotics such asbleomycin hydrochloride, aclarubicin hydrochloride, vinblastine sulfate,etc.; vitamins such as thiamine nitrate, etc. These cationicpharmaceutically active substances may also be in the form ofpharmaceutically acceptable salts thereof or free bases thereof.

In case that the pharmaceutically active substance is a peptide or aprotein, the substance may be either anionic or cationic, depending uponpH of the composition. Accordingly, ionic compounds carrying countercharges can optionally be selected as required, taking into account astable pH region for, e.g., a peptide or a protein. Examples of thepeptide or protein include neocarzinostatin, zinostatin stilamer(SMANCS), interferon (e.g., α, β, γ), interleukin (e.g., IL-1 throughIL-18), tumor necrosis factor (TNF), erythropoietin (EPO), granulocytecolony-stimulating factor (G-CSF), macrophage colony-stimulating factor(M-CSF), granulocyte macrophage colony-stimulating factor (GM-CSF),thrombopoietin (TPO), platlet-derived growth factor, stem cell growthfactor (SCF), basic or acidic fibroblast growth factor (FGF) or a familythereof, nerve growth factor (NGF) or a family thereof, insulin-likegrowth factor (IGF), a super family of osteogenesis factor (e.g., BMP1through BMP12) or transforming growth factor (TGFβ), hepatocyte growthfactor (HGF), platelet-derived growth factor (PDGF), epidermal growthfactor (EGF), insulin, calcitonin, glucagon, human growth hormone (hGH),parathyroid hormone (PTH), L-asparginase, superoxide dismutase (SOD),tissue plasminogen activator (t-PA) and the like. These peptides orproteins may be those having naturally occurring sequences or havealtered sequences. Alternatively, the peptides or proteins may bemodified (e.g., chemically modified with polyethylene glycol). Thepeptides or proteins may also be used as monomers or as homopolymers orheteropolymers.

The anionic pharmaceutically active substances or cationicpharmaceutically active substances are preferably synthetic ionicpharmaceutically active substances. While ionic prostanoic acidderivatives are excluded from the present invention, a certain compoundout of the derivatives, e.g.,(±)-(1R*,2R*,3aS*,8bS*)-2,3,3a,8b-tetrahydro-2-hydroxy-1-[(E)-(3S*)-3-hydroxy-4-methyl-1-octen-6-ynyl]-1H-cyclopenta[b]benzofuran-5-butanoicacid (generic name “beraprost”) or salts thereof, which can be producedby the process described in Japanese Patent Application Laid-Open No.58-124778, may be employed in some occasion for convenience to explainthe effect of the present invention (the sodium salt of beraprost iscommercially available as an anti-platelet agent or a blood flowimproving agent under the generic name “beraprost sodium”, which is alsosometimes abbreviated simply as “BPS”).

The amount of the ionic pharmaceutically active substance used in thepresent invention is not particularly limited, so long as it is withinsuch an amount that generally exhibits a pharmacologically therapeuticeffect. According to the present invention, even though the substance issparingly soluble in water, the ionic pharmaceutically active substancecan enjoy the benefits of sustained release by imparting hydrophobicitythereto, as in readily water-soluble substances.

The ionic compound having an opposite charge to that of the ionicpharmaceutically active substance increasing its hydrophobicity used inthe present invention is not particularly restricted but preferably asubstance containing a highly hydrophobic group(s). The presence ofhighly hydrophobic group(s) in the molecule of the ionic compound canincrease the hydrophobic property of the ionic pharmaceutically activesubstance. The degree of hydrophobicity can be determined by calculatingas an index the oil/water partition coefficient of the pharmaceuticallyactive substance (that is, a ratio of, e.g., the concentration of thepharmaceutically active substance in an oil phase such as octanol to theconcentration of the pharmaceutically active substance in water).Preferably, when the ionic compound is added to the pharmaceuticallyactive substance in such an amount that the compound has a chargeequivalent to that of the pharmaceutically active substance, theoil/water partition coefficient increases as compared to no addition ofthe compound. More preferably, when the compound having a counter ion isadded to the pharmaceutically active substance in an excess amount togive more charges by, e.g., 20 times than equivalent one, the partitioncoefficient increases much more than the addition in an equivalentcharge. The term “ionic” in the ionic compound of the present inventionis used to mean that the compound contains one or more charged groups inthe molecule thereof. The charged group functions as a hydrophilic groupin the molecule. The ionic compound may additionally contain otherhydrophilic groups not associated with charge. Preferably, the ioniccompound contains one charged group in the molecule thereof Where thepharmaceutically active substance is anionic, the cationic compound tobe incorporated preferably contains an ammonium, pyridinium, phosphoniumor sulfonium group in the molecule thereof, or may be in the form oftheir salts. More preferably, the cationic compound contains thefunctional group mentioned above and the functional group carries ahydrophobic group having at least 6 carbon atoms. Examples of suchcationic compounds are trialkylbenzyl ammonium salts such asbenzyltriethylammonium chloride, benzyltributylammonium chloride, etc.;alkyldimethylbenzylammonium salts such as octyldimethylbenzylammoniumchloride, lauryldimethylbenzylammonium chloride,myristyldimethylbenzylammonium chloride, stearyldimethylbenzylammoniumchloride, benzalkonium chloride which is the mixture oflauryldimethylbenzylammonium chloride and myristyldimethylbenzylammoniumchloride; benzethonium chloride or derivatives thereof; alkyltrimethylsalts such as lauryltrimethylammonium chloride, cetyltrimethylammoniumchloride, lauryltrimethylammonium chloride, behenyltrimethylammoniumchloride, etc.; alkyl pyridinium salts such as laurylpyridiniumchloride, cetylpyridinium chloride, etc.; alkylamine salts such asoleylamine acetate, stearylamine acetate, etc.; alkylphosphonium saltssuch as tetrabutylphosphonium chloride,tricetyl(4-vinylbenzyl)phosphonium chloride, etc. or derivativesthereof. Examples of the cationic compounds include surface-activemedicaments such as chlorpromazine hydrochloride, phenothiazine,perphenazine, perphenazine maleate, levomepromazine, lidocainehydrochloride, meprylcaine hydrochloride, acetylcholine chloride,methylbenactyzium bromide, distigmine bromide, torazoline hydrochloride,imipramine hydrochloride, desipramine hydrochloride, amitriptylinehydrochloride, procaine hydrochloride, lidocaine hydrochloride,dibucaine hydrochloride, meprylcaine, diphenhydramine hydrochloride,chlorpheniramine maleate, iproheptine, etc. These cationic compounds maybe in the form of pharmaceutically acceptable salts or free bases.Preferably, the salts are alkyldimethylbenzylammonium salts,alkyldimethylbenzylammonium salts, alkylpyridinium salts, alkylamineslats and alkylphosphonium salts, more preferably,alkyldimethylbenzylammonium salts, most preferably benzalkoniumchlorides. These compounds may be used in combination of two or more.

In case that the pharmaceutically active substance is cationic, theanionic compound added as the ionic compound in the present inventioncontains preferably a carboxyl, sulfate, sulfonate or phosphate group inthe molecule thereof. More preferably, the anionic compound contains thefunctional group(s) described above which carries a hydrophobic group ofat least 6 carbon atoms. Examples of such anionic compounds includehigher fatty acids such as caproic acid, caprylic acid, capric acid,lauric acid, myristic acid, palmitic acid, stearic acid, oleic acid,etc., or physiologically acceptable salts thereof (e.g., sodium orpotassium); alkyl sulfates such as sodium lauryl sulfate, sodiummyristyl sulfate, etc.; alkyl ether sulfates such as POE (2) laurylether sodium sulfate, etc.; alkylallyl sulfonates such as sodium laurylsulfoacetate, etc.; alkyl sulfonates such as sodiumdodecylbenzenesulfonate, etc.; sulfosuccinates; N-acylaminoacid saltssuch as sodium lauroylsarcosine, etc.; alkyl phosphates such as sodiumlaurylphosphate, etc.; alkyl ether phosphates or free acids thereof;bile acids or salts thereof such as sodium deoxycholate, etc.; anddialkylphosphatidinic acid salts such as sodiumdipalmitoylphosphatidinate, etc. or free acids thereof. Preferably, theanionic compounds are sodium oleate and/or sodium laurylsulfate. Thesecompounds may be used in combination of two or more.

The amount of the ionic compound to be added is not particularly limitedso long as the compound is added in such an amount that can generallyneutralize the charge of the pharmaceutically active substance andincrease the hydrophobic property of the pharmaceutically activesubstance. The ionic compound is added preferably in the amount of0.0001% to 50%, more preferably 0.001 to 10%, furthermore preferably0.01 to 5%, all inclusive, in terms of weight/% by weight. The amount ofthe ionic compound to be added can be chosen to be the amount showing adesired sustained release pattern within the physiologically acceptableupper limit. The amount of the ionic compound added can be determinedgenerally in terms of a molar ratio (charge ratio) based on the ionicpharmaceutically active substance and is preferably between 1 and 1,000,inclusive.

With respect to the pH of the sustained-release pharmaceuticalcomposition of the present invention, its pH range is not particularlylimited as far as pH is generally within a physiologically acceptablerange but preferably it is in the range of 3 to 8. The pH can besuitably determined in view of stability of the ionic pharmaceuticallyactive substance used in the invention.

The sustained-release pharmaceutical composition of the presentinvention can be prepared into a variety of pharmaceutical preparationsin the form of, e.g., an aqueous solution, an oily preparation, a fattyemulsion, an emulsion, a gel, etc., and these preparations can beadministered as intramuscular or subcutaneous injection or as injectionto the organ, or as an embedded preparation or as a transmucosalpreparation through nasal cavity, rectum, uterus, vagina, lung, etc. Thecomposition of the present invention can also be administered in theform of oral preparations (e.g., solid preparations such as tablets,capsules, granules or powders; liquid preparations such as syrup,emulsions or suspensions). Inter alia, injecting is a preferred form ofthe preparations. Where the composition is prepared into an injection,the composition may contain, if necessary and desired, a knownpreservative, stabilizer, dispersing agent, pH controller or isotonicagent. Examples of the preservative are glycerin, propylene glycol,phenol, benzyl alcohol, etc. Examples of the stabilizer are dextran,gelatin, tocopherol acetate, alpha-thioglycerin, etc. Examples of thedispersing agent include polyoxyethylene (20) sorbitan monoolelate(Tween 80), sorbitan sesquioleate (Span 30), polyoxyethylene (160)polyoxypropylene (30) glycol (Pluronic F68), polyoxyethylenehydrogenated castor oil 60, etc. Examples of the pH controller includehydrochloric acid, sodium hydroxide, etc. Examples of the isotonic agentare glucose, D-sorbitol, D-mannitol, etc.

The sustained-release pharmaceutical composition of the presentinvention can be administered as an aqueous solution in its originalcomposition since the composition itself exhibits the sustained releaseeffect. In order to further increase the sustained release effect,however, the composition may be formulated with additional componentssuch as vegetable oil, e.g., soybean oil, sesame oil, camellia oil,castor oil, peanut oil, rape seed oil, etc.; middle fatty acidtriglycerides; fatty acid esters such as ethyl oleate; polysiloxanederivatives, etc.; alternatively, water-soluble high molecular weightcompounds such as hyaluronic acid or salts thereof (weight averagemolecular weight: ca. 80,000 to 2,000,000), carboxymethylcellulosesodium (weight average molecular weight: ca. 20,000 to 400,000),hydroxypropylcellulose (viscosity in 2% aqueous solution: 3 to 4,000cps), atherocollagen (weight average molecular weight: ca. 300,000),polyethylene glycol (weight average molecular weight: ca. 400 to20,000), polyethylene oxide (weight average molecular weight: ca.100,000 to 9,000,000), hydroxypropylmethylcellulose (viscosity in 1%aqueous solution: 4 to 100,000 cSt), methylcellulose (viscosity in 2%aqueous solution: 15 to 8,000 cSt), polyvinyl alcohol (viscosity: 2 to100 cSt), polyvinylpyrrolidone (weight average molecular weight: 25,000to 1,200,000), etc.

In the sustained-release pharmaceutical composition of the invention, itis preferred that the ionic pharmaceutically active substance bemaintained in its dissolution state but may be in a suspension, sincethere is no particular limitation to the appearance.

A dose of the sustained-release pharmaceutical composition according tothe present invention may be appropriately chosen, depending upon theamount of the composition or the pharmaceutically active substancecontained in the composition, kind of diseases, age and body weight ofthe patient, frequency of administration, etc. In general, however, thedose is in the range of 0.1 μg to 10 g, preferably 10 μg to 1 g.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows a release behavior of diclofenac in Test 3 to determine therelease of the preparations obtained in Examples 1 and 2 and ComparativeExample 1, which test was carried out in 10 ml of a phosphate buffersolution (pH 7.4) at 37° C.

FIG. 2 shows the concentration of medicaments in plasma plotted withpassage of time in Test 4, when the preparations obtained in Examples 6,11 and Comparative Example 2 were subcutaneously given to Wistar strainmale rats (age of 8 weeks) at the back.

BEST MODE FOR CARRYING OUT THE INVENTION

The present invention will be described below in more detail, withreference to Tests, Examples and Comparative Examples but is not deemedto be limited thereto.

REFERENCE TEST 1 Effect of the Ratio of Benzalkonium Chloride Added andpH on the Octanol/phosphate Buffer Partition Coefficient (PC) of BPS

Method

BPS was dissolved in phosphate buffer solution having pH of 5 to 8 in aconcentration of 240 μg/ml. Various cations were added to the mixturesto give equivalent charge to that of BPS or 5 times or 20 times morethan that of BPS. The same volume of octanol as that of the aqueousphase was added to the mixture followed by shaking at 37° C. for anhour. After centrifugation, the concentration of the pharmaceuticallyactive substance in the aqueous phase was measured to calculate thepartition coefficient.

partition coefficient=concentration of the pharmaceutically activesubstance in the octanol phase/concentration of the pharmaceuticallyactive substance in the aqueous phase

Results and Discussion

As a result, PC increased at pH of 7 as the amount of benzalkoniumchloride added increased. This is considered to be because BPS with itshydrophobic degree being increased by the formation of ion complex isdistributed in the octanol phase so that the equilibrium in the ioncomplex formation occured in the aqueous phase shifted toward thecomplex formation as the concentration of benzalkonium chloride becamehigh. With respect to the pH, the partition coefficient of BPS, which isan acidic substance, decreased as the pH increased but the decrease inpartition coefficient was suppressed by the addition of benzalkoniumchloride. That is, the effect of benzalkonium chloride on the partitioncoefficient of BPS was greater in the high pH. When sodium chloride wasadded to make the solution isotonic, in which 20 times of equivalentmolar ratio of benzalkonium chloride was included, the partitioncoefficient of BPS decreased. This is believed to be because theformation of ionic complex would be inhibited by the addition of sodiumchloride. It was thus supported that the formation of ionic complexparticipated in the effect of enhancing the partition coefficient of BPSachieved by the addition of benzalkonium chloride.

TEST 1 Evaluation of Cationic Compound by Test in Terms of PartitionCoefficient

A variety of cations were examined with their effect if these cationswould affect the partition coefficient of diclofenac sodium (hereinaftersometimes simply referred to as “DIC”) in octanol/phosphate buffersolution (pH 7).

Method

The pharmaceutically active substance was dissolved in an aqueous phasein a concentration of 240 μg/ml. Various cations were added to thesolution to give equal charge to that of DIC or charges 20 times morethan that of DIC. Then the same procedure as in Reference Test 1 wasapplied to calculate the partition coefficient.

Results and Discussion

With regard to the effect of various cations on the partitioncoefficient of the pharmaceutically active substance, representativeresults are shown in Table 1. An increase in the partition coefficientof he anionic pharmaceutically active substance was noted withalkylbenzylammonium salts such as triethylbenzylammonium chloride, etc.,alkyltrimethylammonium salts such as lauryltrimetnylammonium chloride,etc.; phosphonium salts, lidocaine hydrochloride and meprylcainehydrochloride. However, the partition coefficient of DIC showed nochange with sorbitan sesquioleate (Span 30), which is a nonioniccompound, and sodium lauryl sulfate, which is an anionic compound, forcomparison, as compared to the partition coefficient when any ioniccompound was not added (data not shown in Table 1); the results indicatethat no effect was observed with the comparative compounds. Turning tothe inorganic salts (magnesium chloride) or the compound having a smalllevel of hydrophobicity (arginine hydrochloride), these compounds couldform complexes but failed to enhance the hydrophobic property of DIC.Thus, no increase in the partition coefficient was noted. Furthermore,cationic hydroxyethylcellulose (Kachi-sero H-60, produced by Kao Corp.,Japan) and protamine sulfate did not affect the partition coefficient;it is likely that these compounds contain hydrophilic groups representedby cationic groups so that overall the highly hydrophilic nature ofmolecules is presented with respect to the other hydrophobic groupspresent in the molecule and for this reason, the hydrophobic property ofthe pharmaceutically active substance would not be given enough even ifcomplexes are formed.

TABLE 1 PC of BPS PC of DIC Equimolar Excess Equimolar Excess Cationadded amount × 20 amount × 20 Triethylbenzylammonium — — 14.0 25.7chloride Tributylbenzylammonium 24.5 140 42.9 1030 chlorideOctyldimethylbenzylammonium 60.9 568 75.5 6220 clorideLauryldimethylbenzylammonium 71.2 1220 2780 12000 chlorideMyristyldimethylbenzylammonium 64.5 1210 110 12300 chlorideStearyldimethylbenzylammonium 62.3 1350 1850 9640 chloride Benzethoniumchloride 70.8 1180 54.6 9320 Lauryltrimethylammonium 83.5 985 596 11700chloride Cetyltrimethylammonium 91.6 935 490 7690 chlorideStearyltrimethylammonium 83.4 995 1050 7190 chlorideBehenyltrimethylammonium 59.5 — 1120 — chloride Laurylpyridiniumchloride 75.0 1200 239 — Cetylpyridinium chloride 77.8 1070 255 9060Oleylamine acetate 30.4 473 62.2 3700 Stearylamine acetate 32.6 158 97.31020 Lidocaine hydrochloride 17.1 37.5 13.9 51.0 Meprylcainehydrochloride 17.7 53.3 16.8 209 Tetrabutylphosphonium — — 45.2 1190chloride Tricetyl — — 164 10300 (4-vinylbenzyl)phoshphonium choride None16.2 13.1

That is, the results reveal that where the pharmaceutically activesubstance is anionic, the compounds having opposite charges such asquaternary ammonium or phosphonium groups and highly hydrophobicsubstutients (e.g., hydrophobic groups of 6 or more carbon atoms)exhibit the effect of increasing the hydrophobic property of the anionicpharmaceutically active substance.

REFERENCE TEST 2 Evaluation of Cationic Compound by Test in Terms ofPartition Coefficient

A variety of cations were examined with their effect if these cationswould affect the partition coefficient of BPS in octanol/phosphatebuffer solution (pH 7).

Method as well as Results and discussion are the same as in Test 1. Theresults obtained are shown in Table 1 together with those of Test 1.

TEST 2 Evaluation of Anionic Compound by Test in Terms of PartitionCoefficient

A variety of anions were examined with their effect if these anionswould affect the partition coefficient of tamsulosin hydrochloride inoctanol/phosphate buffer solution (pH 7).

Method

Tamsulosin hydrochloride was dissolved in an aqueous phase in aconcentration of 100 μg/ml. Various anions were added to the mixtures togive equal charge to and charges larger by 5 times and 20 times thanthat of the medicament. Thereafter the same procedure was performed asin Reference Test 1 and the partition coefficient was calculated.

Results and Discussion

With regard to the effect of various anions on the partition coefficientof tamsulosin hydrochloride, representative results are shown in Table2. The partition coefficient increased in the fatty acids or saltsthereof (sodium salts in this test) in correlation to the additionamount (none, equimolar, ×20). In particular, sodium lauryl sulfate,which is an alkyl sulfonate, showed the highest partition coefficient.However, Span 30 which is a nonionic compound, and benzalkonium chloridewhich is a cationic compound, used for comparison, showed the partitioncoefficient equivalent to or lower than the partition coefficient whenno ionic compound was added (data not shown in Table 2). No increase inthe partition coefficient was noted with tartaric acid, suberic acid,sebacic acid carboxymethylcellulose sodium (CMC-Na), sodium hyaluronateand Eudragit® L. This is believed because in these compounds thehydrophilic property is stronger in view of the balance between thehydrophilic and hydrophobic groups contained so that the hydrophobicproperty of the pharmaceutically active substance did not increaseenough, even though the complex was formed.

TABLE 2 Partition coefficient of tamsulosin hydrochloride EquimolarAnion added amount Excess (x20) Sodium caproate 4.21 4.93 Sodiumcaprylate 4.55 6.28 Sodium caprate 4.48 5.74 Sodium laurate — 8.87Sodium oleate — 5.38 Sodium deoxycholate 4.18 4.82 Sodium lauryl sulfate5.93 85.0  None 3.87

The above results reveal that where the pharmaceutically activesubstance is cationic, the compounds having opposite charges such ascarboxyl or sulfate groups and highly hydrophobic substutients (e.g.,hydrophobic groups of 6 or more carbon atoms) exhibit the effect ofincreasing the hydrophobic property of the cationic pharmaceuticallyactive substance.

EXAMPLES 1 AND 2

Gel Preparation

After 0.1 part of DIC and 0.36 part of a cationic compound (benzalkoniumchloride or cetyltrimethylammonium chloride) were dissolved in 89.54parts of water, 10 parts of HPC-M was added to the solution. The mixturewas stirred and fully swollen to give a gel preparation (Table 3).

TABLE 3 Example 1 2 DIC 0.1 0.1 Benzalkonium chloride 0.36 —Cetyltrimethylammonium chloride — 0.36 HPC-M 10 10 Water 89.54 89.54

Comparative Example 1

A gel preparation for comparison was prepared in a manner similar toExample 1 except that no benzalkonium chloride was added.

EXAMPLES 3 THROUGH 7

Gel Preparation

After 0.1 part of DIC and benzalkonium chloride were dissolved in water,5 parts of HPC-M was added to the solution. The mixture was stirred andfully swollen to give a gel preparation (Table 4).

TABLE 4 Example 3 4 5 6 7 DIC 0.1 0.1 0.1 0.1 0.1 Benzalkonium chloride0.11 0.36 1.1 2.2 5.5 HPC-M 5 5 5 5 5 Water 94.79 94.54 93.8 92.7 89.4

EXAMPLES 8 THROUGH 11 Liquid Preparation

In water, 0.1 part of DIC and benzalkonium chloride were dissolved togive a liquid preparation (Table 5).

TABLE 5 Example 8 9 10 11 DIC 0.1 0.1 0.1 0.1 Benzalkonium chloride 0.110.36 1.1 2.2 Water to make 100 100 100 100

Comparative Example 2

A liquid preparation for comparison was prepared in a manner similar toExamples 8 through 11 except that no benzalkonium chloride was added.

EXAMPLES 12 THROUGH 15

Gel Preparation

After the anionic pharmaceutically active substance (sodium salicylate,calcium fenoprofen) and the cationic compound (benzalkonium chloride,cetyltrimethylammonium chloride) were dissolved in water, 10 parts ofHPC-M was added to the solution. The mixture was stirred and fullyswollen to give a gel preparation (Table 6).

TABLE 6 Example 12 13 14 15 Sodium salicylate 0.02 0.02 — — Calciumfenoprofen — — 0.02 0.02 Benzalkonium chloride 0.36 — 0.36 —Cetyltrimethylammonium chloride — 0.36 — 0.36 HPC-M 10 10 10 10 Water89.62 89.62 89.62 89.62

EXAMPLES 16 THROUGH 18

Gel Preparation

After the anionic pharmaceutically active substance (sodium cefpiramid,minodronic acid) and the cationic compound (benzalkonium chloride,cetyltrimethylammonium chloride) were dissolved in water, 10 parts ofHPC-M was added to the solution. The mixture was stirred and fullyswollen to give a gel preparation (Table 7).

TABLE 7 Example 16 17 18 Sodium cefpiramid 0.02 0.02 — Minodronic acid —— 0.02 Benzalkonium chloride 0.36 — 0.36 Cetyltrimethylammonium chloride— 0.36 — HPC-M 10 10 10 Water 89.62 89.62 89.62

EXAMPLES 19 THROUGH 22

Gel Preparation

After the cationic pharmaceutically active substance (tamsulosinhydrochloride, ramosetron hydrochloride) and the anionic compound(sodium oleate, sodium lauryl sulfate) were dissolved in water, 10 partsof HPC-M was added to the solution. The mixture was stirred and fullyswollen to give a gel preparation (Table 8).

TABLE 8 Example 19 20 21 22 Tamsulosin hydrochloride 0.02 0.02 — —Ramosetron hydrochloride — — 0.02 0.02 Sodium oleate 0.36 — 0.36 —Sodium lauryl sulfate — 0.36 — 0.36 HPC-M 10 10 10 10 Water 89.62 89.6289.62 89.62

Comparative Example 3

A gel preparation for comparison was prepared in a manner similar toExamples 19 and 20 except that no sodium oleate or sodium lauryl sulfatewas added.

TEST 3

Effect of Release Test In Vitro

Each of the gel preparations obtained in Examples 1 and 2, ComparativeExample 1 and Examples 12, 13, 14, 15,16, 17 and 18 was assessed,respectively, with regard to the release of the active substance in 10ml of a phosphate buffer solution (pH 7.4) at 37° C.

The results of the release test are shown in FIG. 1. According to theresults, a delayed release was confirmed with the quaternary ammoniumsalt with the hydrophobic property being enhanced in the partitioncoefficient test, while no delayed release was noted in some ofComparative Examples.

TEST 4

In Vivo Effect in Rat(Effect of the Amount of Cations Added)

The gel preparations of Examples 3 to 7, the liquid preparations ofExamples 8 to 11 and Comparative Example 2 were subcutaneously given toWistar strain male rats (age of 8 weeks) at the back, respectively, todetermine the concentration of the active substance in plasma withpassage of time.

The results are shown in FIG. 2 in terms of the plasma concentrationwith passage of time. According to the results, the change in plasmaconcentration of the active substance shows a sustained release patternwith correlation to the amount of benzalkonium chloride added,suggesting that the sustained release pattern can be controlled bychanging the addition amount. On the contrary, no sustained release wasnoted with some of Comparative Examples.

TEST 5

Effect of Release Test In Vitro

Each of the gel preparations obtained in Examples 19 and 20, ComparativeExample 3 and Examples 21 and 22 was assessed, respectively, with regardto the release of the active substance in 10 ml of a phosphate buffersolution (pH 7.4) at 37° C.

According to the results, a delayed release was confirmed with the alkylorganic acid salts which were shown to have enhanced hydrophobicproperty in the partition coefficient test, while no delayed release wasnoted in some of Comparative Example.

REFERENCE EXAMPLE 1

Gel Preparation

After 0.024 part by weight (hereinafter merely referred to as “part”) ofBPS and 0.29 part of capryldimethylbenzylammonium chloride (which molaramount was adjusted to correspond to 0.36 part of benzalkonium chloride)were dissolved in 89.686 parts of water, 10 parts ofhydroxypropylcellulose (trademark: HPC-M) was added to the solution. Themixture was stirred and fully swollen to give a gel preparation.

REFERENCE EXAMPLES 2 THROUGH 9

Gel Preparation

Gel preparations having the same parts as in Reference Example 1 wereprepared in a manner similar to Reference Example 1 except thatcapryldimethylbenzylammonium chloride of Reference Example 1 wasreplaced by other cationic compounds shown in Table 9.

TABLE 9 Reference Example Cationic compound 2Lauryldimethylbenzylammonium chloride 3 Myristyldimethylbenzylammoniumchloride 4 Stearyldimethylbenzylammonium chloride 5Lauryltrimethylammonium chloride 6 Cetyltrimethylammonium chloride 7Stearyltrimethylammonium chloride 8 Behenyltrimethylammonium chloride 9Benzethonium chloride

Comparative Reference Examples 1 Through 3

After 0.024 part of BPS was dissolved in water, 10 parts of HPC-M wasadded to the solution. The mixture was stirred and fully swollen to givea gel preparation. Furthermore, arginine hydrochloride and magnesiumsulfate were added to the above preparation, respectively to give gelpreparations. These preparations were used as comparative referencesamples (Table 10).

TABLE 10 Comparative Reference 1 2 3 BPS 0.024 0.024 0.024 Argininehydrochloride — 0.1 — Magnesium sulfate 7H₂O — — 0.1 HPC-M 10 10 10Water 89.976 89.876 89.876

REFERENCE TEST 3

In Vitro Release Test of Gel Preparation Using Various Cations

Each of the gel preparations obtained in Reference Examples 1 to 9 andComparative Reference Examples 1 to 3 was evaluated, respectively, withregard to the release of the active substance in 10 ml of a phosphatebuffer solution (pH 7.4) at 37° C.

According to the results, a delayed release was confirmed with thequaternary ammonium salt that was shown to enhance the hydrophobicproperty in the partition coefficient test (Reference Test 2). On theother hand, no delayed release was noted with magnesium sulfate andarginine hydrochloride in the reference test, which are divalentinorganic metal salts similar to magnesium chloride demonstrated tohardly enhance the partition coefficient. These results thus suggestthat there is a correlation between the effect of enhancing thepartition coefficient and the sustained release effect.

REFERENCE EXAMPLE 10

Gel Preparation

After 0.024 part of BPS and 0.02 part of benzalkonium chloride weredissolved in 89.956 parts of water, 10 parts of HPC-M was added to thesolution. The mixture was stirred and fully swollen to give a gelpreparation.

REFERENCE EXAMPLES 11 THROUGH 17

Gel Preparation

Gel preparations having the amounts of BPS, benzalkonium chloride, HPC-Mand water shown in Table 11 were prepared in a manner similar toReference Example 10.

Comparative Reference Example 4

A gel preparation for comparison was prepared in a manner similar toReference Example 17 except that no benzalkonium chloride was added.

TABLE 11 Reference Example 11 12 13 14 15 16 17 BPS 0.024 0.024 0.0240.002 0.002 0.002 0.002 Benzalkonium 0.1 0.2 0.36 0.002 0.1 0.2 0.36chloride HPC-M 10 10 10 5 5 5 5 Water 89.876 89.776 89.616 94.996 94.89894.798 94.638

REFERENCE TEST 4

Effect of the Amount of Counter Ions Added on Release in Gel Preparation

Release test was carried out in 10 ml of a phosphate buffer solution (pH7.4) at 37° C., using the preparations obtained in Reference Examples 11Through 13 and Comparative Reference Example 1.

The results reveal that release of BPS from the preparation of thepresent invention was apparently controlled as compared to theComparative Reference Example and the release was delayed in correlationto the addition amount of benzalkonium chloride, which is a counter ion.

REFERENCE TEST 5

Effect of the Addition Amount of Benzalkonium Chloride in Rat In Vivo

The gel preparations obtained in Reference Example 17 and ComparativeReference Example 4 were subcutaneously given to Wistar strain male rats(age of 8 weeks) at the back, respectively. The concentration of theactive substance in plasma was determined with passage of time.

In the preparation of the present invention (added with benzalkoniumchloride), the change in plasma concentration of the active substanceshowed a sustained release as compared to the comparative example. It isconsidered also from the foregoing results in vitro (Reference Test 4)that the sustained release pattern can be controlled by changing theamount of benzalkonium chloride added.

REFERENCE EXAMPLE 18

Liquid Preparation

In 99.638 parts of water, 0.002 part of BPS and 0.36 part ofbenzalkonium chloride were dissolved to give a liquid preparation.

Comparative Reference Example 5

Liquid Preparation

A liquid preparation for comparison was prepared in a manner similar toReference Example 18 except that no benzalkonium chloride was added.

REFERENCE EXAMPLE 19

Emulsion Preparation

After 0.002 part of BPS and 0.36 part of benzalkonium chloride weredissolved in 94.638 parts of water, 5 parts of soybean oil was added tothe solution. An emulsion preparation was prepared using amicrofluidizer (12,000 psi, 10 minutes at room temperature).

REFERENCE EXAMPLES 20 THROUGH 24

Emulsion Preparation

Emulsion preparations having the amounts of BPS, benzalkonium chloride,other additives (surfactant, oil, etc.) and water shown in Table 12 wereprepared in a manner similar to Reference Example 19.

TABLE 12 Reference Example 20 21 22 23 24 BPS 0.002 0.002 0.002 0.0020.002 Benzalkonium 0.36 0.36 0.36 0.36 0.36 chloride Pluronic F68 1.8 —— 1.8 — Tween 80 — 1.8 — — 1.8 Soybean oil 10 10 — — — Sesame oil — — 510 10 Concentrated glycerin 2.21 2.21 — 2.21 2.21 Water to make 100 100100 100 100

REFERENCE EXAMPLE 25

After 0.002 part of BPS and 0.36 part of benzalkonium chloride weredissolved in 2 parts of ethanol, soybean oil was added to the solutionto make the volume 100 parts. Thus, an oily preparation was prepared.

REFERENCE EXAMPLES 26 THROUGH 30

Oily Preparation

After BPS and benzalkonium chloride were dissolved in alcohols (ethanol,benzyl alcohol, benzyl benzoate), oil (soybean oil, sesame oil) wasadded to the solution, all in the amount indicated in Table 13, to makethe volume 100 parts. Thus, oily preparations were prepared.

TABLE 13 Reference Example 26 27 28 29 30 BPS 0.002 0.002 0.002 0.0020.002 Benzalkonium 0.36 0.36 0.36 0.36 0.36 chloride Ethanol — — 2 — —Benzyl alcohol 2 5 — 2 5 Benzylbenzoate 20 — — 20 — Soybean oil to make100 100 — — — Sesame oil to make — — 100 100 100

REFERENCE EXAMPLES 31 THROUGH 34

Gel Preparation

After 0.002 part of BPS and 0.36 part of benzalkonium chloride weredissolved in water, a gel base (CMC-Na, sodium hyaluronate,atherocollagen, gelatin) was added to the solution. The mixture wasstirred and fully swollen to give gel preparations Cable 14).

TABLE 14 Reference Example 31 32 33 34 BPS 0.002 0.002 0.002 0.002Benzalkonium 0.36 0.36 0.36 0.36 chloride CMC-Na 3 — — — Na hyaluronate— 2.5 — — Atherocollagen — — 2 — Gelatin — — — 10 Water 96.638 97.13897.638 89.638

REFERENCE EXAMPLES 35 THROUGH 38

Cream Preparation

After 0.002 part of BPS and 0.36 part of benzalkonium chloride weredissolved in water, a gel base (HPC-M, CMC-Na, sodium hyaluronate,atherocollagen) was added to the solution. The mixture was stirred togive cream preparations (Table 15).

TABLE 15 Reference Example 35 36 37 38 BPS 0.002 0.002 0.002 0.002Benzalkonium 0.36 0.36 0.36 0.36 chloride HPC-M 5 — — — CMC-Na — 3 — —Na hyaluronate — — 2.5 — Atherocollagen — — — 2 Water 74.638 76.63877.138 77.638 Soybean oil 20 20 20 20

REFERENCE TEST 6

In Vivo Effect in Rat

Each of the liquid preparations obtained in Reference Example 18 andComparative Reference Example 5, the emulsion preparations of ReferenceExamples 19 to 21, the oily preparations obtained in Reference Examples25 to 28 and the gel preparations or cream preparations obtained inReference Examples 31 to 38 was subcutaneously given to Wistar strainmale rats (age of 8 weeks) at the back to determine the concentration ofthe active substance in plasma with passage of time.

The results reveal that the sustained release effect was obtained withthe respective preparations, by adding counter ions. To the contrary, nosustained release effect was noted with some of the ComparativeReference Examples.

INDUSTRIAL APPLICABILITY

The present invention is useful as providing the sustained-releasepharmaceutical composition which exhibits excellent sustained releaseeffect of the ionic pharmaceutically active substance (excluding ionicprostanoic acid derivatives), irrespective of water solubility possessedby the ionic pharmaceutically active substance. The sustained releaseaccording to the present invention is effected by means of a techniquequite different from conventional techniques including those adopted tosustain the release of ionic pharmaceutically active substances, toinsolubilize a pharmaceutically active substance itself and to retarddissolution of such a substance by microencapsulation. The presentinvention is also useful in that the sustained release can be achievedby the invention to a fully satisfactory extent that was not obtained byknown techniques.

The pharmaceutical composition of the present invention can attainexcellent sustained release effect not only in the form of injection butalso in all other pharmaceutical preparations including implants,transmucosal and oral preparations.

What is claimed is:
 1. A sustained-release pharmaceutical compositionfor an ionic pharmaceutically active substance comprising an ionicpharmaceutically active substance (excluding an ionic prostanoic acidderivative) and an ionic compound having an opposite charge to that ofthe ionic pharmaceutically active substance and increasinghydrophobicity of the active substance, wherein the ionic compound isincorporated at least in an equimolar amount based on thepharmaceutically active substance in terms of a charge ratio.
 2. Asustained-release pharmaceutical composition according to claim 1,wherein the ionic compound having an opposite charge to the ionicpharmaceutically active substance and increasing the hydrophobicproperty of the active substance contains a hydrophobic group in themolecule thereof.
 3. A sustained-release pharmaceutical compositionaccording to claim 1, wherein the ionic compound increases an oil/waterpartition coefficient of the ionic pharmaceutically active substance. 4.A sustained-release pharmaceutical composition according to claim 1,wherein the ionic pharmaceutically active substance is anionic.
 5. Asustained-release pharmaceutical composition according to claim 4,wherein the ionic compound is a compound containing a group selectedfrom an ammonium, pyridinium, phosphonium and sulfonium group in themolecule thereof, or a salt thereof.
 6. A sustained-releasepharmaceutical composition according to claim 5, wherein the ioniccompound contains at least one member selected from the group consistingof an alkyldimethylbenzylammonium salt, an alkyltrimethylammonium salt,an alkylpyridinium salt, an alkylamine salt and an alkylphosphoniumsalt.
 7. A sustained-release pharmaceutical composition according toclaim 1, wherein the ionic compound is benzalkonium chloride.
 8. Asustained-release pharmaceutical composition according to claim 4,wherein the ionic pharmaceutically active substance is a synthetic ionicpharmaceutically active substance.
 9. A sustained-release pharmaceuticalcomposition according to claim 1, wherein the ionic pharmaceuticallyactive substance is cationic.
 10. A sustained-release pharmaceuticalcomposition according to claim 9, wherein the ionic compound is acompound containing a group selected from a carboxyl, sulfate, sulfonateand phosphate groups in the molecule thereof, or a salt thereof.
 11. Asustained-release pharmaceutical composition according to claim 10,wherein the ionic compound is sodium lauryl sulfate and/or sodiumoleate.
 12. A sustained-release pharmaceutical composition according toclaim 9, wherein the ionic pharmaceutically active substance is asynthetic ionic pharmaceutically active substance.